Technical Field
The present invention generally relates to methods and compounds for preparing quinazoline and quinazoline derivatives using chemo and/or regioselective metalation reactions.
Background
The heterocyclyl fused ring scaffold of quinazoline has drawn interest in the field of pharmaceutical chemistry because of the diverse range of biological properties exhibited by compounds derived from such a substrate. Quinazoline scaffolds containing various substitution patterns are considered to be of important synthetic chemical as well as physiological importance. The range of biological activity exhibited by this class of compounds, and derivatives thereof, is wide and diverse, showing anticancer, antifungal, and antibacterial activity among many others. (Asif, M. Int. J. Med. Chem. 2014, 395637, 1-27). Accordingly, because of the complexity of functionalization and substitution patterns associated with pharmaceuticals, a synthetic method for selective functionalization of quinazoline scaffolds for use in synthesis of quinazoline derivatives is very valuable.
Given recent advancements in organometallic chemistry, functionalization via organometallic intermediates has become an important tool for synthesis of pharmaceutical products. Specifically, organozinc intermediates serve as an important synthetic species as they are compatible with a wide range of functional groups and afford desired products in high yields. Preparation of heteroaryl zinc intermediates is achieved by three general procedures; (1) insertion of zinc to heteroaryl iodides or bromides, (2) direct insertion of magnesium into heteroaryl halides with zinc (II) salts present, and (3) metalation with (tmp)2Zn.2MgCl2.2LiCl. (Knochel, P.; Schade, M. A.; Bernhardt, S.; Manolikakes, G.; Metzger, A.; Piller, F. M.; Rohbogner, C. J.; Mosrin, M. Beilstein J. Org. Chem. 2011, 7, 1261-1277). Due to the low reactivity afforded by the carbon-zinc bond, the assistance of a transition metal catalyst is sometimes required to facilitate a reaction with an electrophile (i.e., via a Negishi cross-coupling; Wunderlich, S. H.; Knochel, P. Angew. Chem. Int. Ed. 2007, 46, 7685-7688).
Recently, heterocyclyl mixed metal bases have been developed for use in forming zinc intermediates via direct metalation. Those bases are related to the third procedure mentioned above (i.e., metalation with (tmp)2Zn.2MgCl2.2LiCl) and have been reported to achieve chemo and regioselective metalations (Yus, M.; Foubelo, F. Handbook of Functionalized Organometallics; Knochel, P., Ed.; Wiley-VCH: Weinheim, Germany, 2005). However, this strategy has drawbacks. Specifically, only recently has this specific heterocyclyl mixed metal base been discovered so its synthetic methodology is relatively new and unpredictable (Knochel, P.; Schade, M. A.; Bernhardt, S.; Manolikakes, G.; Metzger, A.; Piller, F. M.; Rohbogner, C. J.; Mosrin, M. Beilstein J. Org. Chem. 2011, 7, 1261-1277). In some instances, high temperature and/or microwave irradiation is required to assist zinc metalation reactions that use (tmp)2Zn.2MgCl2.2LiCl (Wunderlich, S.; Knochel, P. Org. Lett. 2008, 10(20) 4705-4707). As of yet, there does not appear to be a way to accurately predict whether a specific scaffold will require high temperature or microwave irradiation to afford zincated synthetic intermediates in a regiospecific manner. Accordingly, although it appears the use of zincated intermediates tolerates most functional groups, certain substrates, sensitive to high temperatures or microwave irradiation, may complicate the use of this reaction strategy.
There have been some reported instances of organometallic chemistry relating to a quinazoline scaffolds, and derivatives thereof. One reported instance of organometallic chemistry related to selective lithiation of quinazoline. (Plé, N.; Turck, A.; Chapouland, V.; Quéguiner, G. Tetrahedron 1997, 53, 2871). While it would initially appear to be somewhat analogous to a zincation strategy, it is also known that aryl lithium species are highly reactive, and are not compatible in the presence of sensitive functional groups like esters or ketones (Yus, M.; Foubelo, F. Handbook of Functionalized Organometallics; Knochel, P., Ed.; Wiley-VCH: Weinheim, Germany, 2005; Vol. 1). As such, a pathway that makes use of a lithiated quinazoline intermediate would have only limited value in a synthetic strategy. Accordingly, lithiation of quinazolines would not be an ideal candidate for a scaffold containing incompatible functional groups like esters or ketones.
While various methods exist for preparing quinazoline compounds, there remains a need in the art for an improved methods and compounds for preparation of various functionalized quinazoline scaffolds. The present disclosure provides these and other related advantages.